The thymic microenvironment in patients with severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) who have failed to develop T cells after haploidentical bone marrow transplantation is markedly abnormal. In SCID patients, thymic epithelial (TE) cell maturation in vivo is arrested, and we have shown that constitutive thymic microenvironment cytokine production is abnormal. However, in vitro cultured SCID thymic stromal cells behave normally in assays of TE cell function (adhesion, growth requirements, support of thymic dendritic cell maturation) indicating that the non-lymphoid thymic microenvironment components other than TE cells may also be important in regulating thymopoiesis. While the epithelial and fibroblast components of the thymus are known to have properties that are necessary for T cell maturation, recent work from our and other laboratories has defined that thymic dendritic cells (TDC) have a unique phenotype and express a number of chemokines that are limited to or most strongly expressed in the thymus, indicating a potentially important role for TDC and/or their products in thymus-specific functions. We hypothesize that one of the functions of TDC is to direct the trafficking of leukocytes to, within, and from the thymus. Our preliminary data that TDC are present, but are markedly diminished in number, in SCID thymuses suggests that TDC development may be defective and play a role in the lack of thymopoiesis in SCID. The goals of the studies described here are to define the role of the TDC in immune reconstitution in SCID, and in collaboration with project 1 to clarify the roles the thymus versus the peripheral T cell play in restoration of immune function in transplanted SCID patients. Our specific aims are to: 1) determine if T-cell reconstitution in SCID after haploidentical T-cell depleted bone marrow transplantation is due to T cell development from bone marrow-derived progenitors or peripheral expansion by testing for the presence of TCR rearrangement excision circles (TRECs) in PB T cells; 2) examine TDC ontogeny in normal and SCID thymus; and 3) define the roles of thymus-specific chemokines in intrathymic T cell development.